Forced Expression of α-Myosin Heavy Chain in the Rabbit Ventricle Results in Cardioprotection Under Cardiomyopathic Conditions
Open accessAbstract
Background— The biochemical differences between the 2 mammalian cardiac myosin heavy chains (MHCs), α-MHC and β-MHC, are well described, but the physiological consequences of basal isoform expression and isoform shifts in response to altered cardiac load are not clearly understood. Mature human ventricle contains primarily the β-MHC isoform. However, the α-MHC isoform can be detected in healthy human ventricle and appears to be significantly downregulated in failing hearts. The unique biochemical properties of the α-MHC isoform might offer functional advantages in a failing heart that is expressing only the β-MHC isoform. This hypothesis cannot be tested in mice or rats because both species express α-MHC as the predominant isoform. Methods and Results— To test the effects of persistent α-MHC expression on the background of β-MHC, we made transgenic (TG) rabbits that expressed rabbit α-MHC cDNA in the ventricle so that the endogenous myosin was partially replaced by the transgenically encoded species. Molecular, histological, and functional analyses showed no significant baseline effects in the TG rabbits compared with nontransgenic (NTG) littermates. To determine whether α-MHC expression afforded any advantages to stressed myocardium, a cohort of TG and NTG rabbits was subjected to rapid ventricular pacing. Although both the TG and NTG rabbits developed dilated cardiomyopathy, the TG rabbits had a higher shortening fraction, less septal thinning, and more normal ±dP/dt than paced NTG rabbits. Conclusions— Transgenic expression of α-MHC does not have any apparent detrimental effects under basal conditions and is cardioprotective in experimental tachycardia-induced cardiomyopathy.
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Rabbit ventricles predominantly express beta-MHC (88% to >95%), similar to human ventricles (>90-95%).
“Rabbit ventricles predominately express β-MHC (88% to >95%) (Hamilton & Ianuzzo, 1991; James, et al., 2005; Suzuki, et al., 2009) similar to humans (>90–95%) (Miyata, et al., 2000; Reiser, et al., 2001).”
From Small and large animal models in cardiac contraction research: advantages and disadvantages (2014) · cites this paper as James, et al., 2005
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Small and large animal models in cardiac contraction research: advantages and disadvantages
Milani-Nejad, N., & Janssen, P. M. L. (2014) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2013.10.007 · Cited by 484 · see citing works
Development of dilated cardiomyopathy in<i>Bmal1</i>-deficient mice
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- Authors
- James, J., Martin, L., Krenz, M., Quatman, C., Jones, F., Klevitsky, R., Gulick, J., & Robbins, J.
- Affiliations
- Cincinnati Children's Hospital Medical Center (US)
- Venue
- Circulation
- Published
- 2005-05-10
- Volume
- 111
- Issue
- 18
- Pages
- 2339-2346
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC1314981
- OpenAlex
- W2130574722
- Cited by
- 77
- References
- 28
- Citations by year
- 2026: 1 · 2024: 4 · 2023: 1 · 2022: 4 · 2021: 2 · 2020: 4 · 2019: 1 · 2018: 2 · 2017: 2 · 2016: 4 · 2015: 3 · 2014: 4 · 2013: 3 · 2012: 5
- FWCI
- 3.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r01hl060546-04)
- National Heart, Lung, and Blood Institute (HL 69799, P01HL069779, HL-56370, HL 60546, R01HL056370, HL 52318, P50HL052318)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- alpha-myosin heavy chain, beta-myosin heavy chain, myosin heavy chain isoforms, cardiomyopathy, dilated cardiomyopathy, rapid ventricular pacing, tachycardia-induced cardiomyopathy, cardioprotection, transgenic rabbits, ventricular function, heart failure
- MeSH terms
- Animals, Cardiac Pacing, Artificial, Cardiomyopathy, Dilated, Cardiotonic Agents, Heart Ventricles, Rabbits, Stress, Physiological, Tachycardia, Gene Expression, Myosin Heavy Chains, Protein Isoforms, Animals, Genetically Modified
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